While antibody-drug conjugates (ADCs), such as fam-trastuzumab deruxtecan-nxki (Enhertu), may have shown efficacy in patients with HER2-low breast cancer in initial studies, according to Sara M.Tolaney, MD, MPH, investigators still need better methods for identifying this disease subtype to guide treatment decisions.

What we're learning is that we really need to improve our ability to detect very low levels of HER2 expression, said Tolaney. Testing will need to change so that we can potentially address all patients who are able to benefit from these therapies.

In an interview with OncLive, Tolaney, associate director of the Susan F. Smith Center for Womens Cancers; director of Clinical Trials, Breast Oncology;andsenior physician at Dana-Farber Cancer Institute, as well as anassistant professor of medicine at Harvard Medical School, discussed the challenges in treating patients with heterogenous HER2 expression and what treatments could potentially improve outcomes for this subgroup.

Tolaney: Some challenges that we face surround the patients who have heterogeneous expression for HER2. For example, it's not that the entire tumor is strongly HER2-positive. We've learned from a couple trials, 1 of them being the KRISTINE trial, and another that is exploring heterogeneity in the preoperative setting, that having heterogeneous HER2 expression can impact the efficacy of ado-trastuzumab emtansine [T-DM1; Kadcyla].

The other challenge is: What about patients who, for example, lose HER2 expression after preoperative therapy? Many of us are uncertain with what to do with those patients who have residual disease, but at the time of surgery are no longer HER2-positive. We did see some data from the KATHERINE study, which showed that even those patients who had HER2-negative disease at the time of surgery, despite being HER2-positive prior to preoperative therapy, still benefited from adjuvant T-DM1, which was quite interesting. There are all of these complexities that come up when caring for patients, but again, we're quite fortunate to have so many nice treatment options in this setting.

HER2-low is defined as tumors with a little bit of HER2 expression but aren't quite HER2-positive. What that means is that if a patient, for example, has a tumor that is 1+ by immunohistochemistry [IHC], we would consider them HER2-lowpositive. If they're HER2 2+ by IHC and is not amplified via fluorescence in situ hybridization [FISH], we would also consider them HER2-lowpositive.

We've seen from various datasets that about 55% of all breast cancers are actually HER2-low, which is a significant proportion of our patients with breast cancer. We do know that the prevalence is different by hormone receptor [HR] expression. [About 60% of] HR-positive tumors are more commonly HER2-lowpositive, as opposed to triple-negative breast cancers where only about one-third of those cases will end up being HER2-lowpositive. The prevalence is different based on breast cancer subtype.

We've seen some initial attempts looking to see if trastuzumab [Herceptin] would have any benefit in patients with a little bit of HER2 expression. We have seen data from a randomized phase 3 trial where, in fact, there was no benefit from trastuzumab added to chemotherapy in the early breast cancer setting for patients with HER2-lowpositive [disease].

What we have seen now is that some of the new ADCs do have activity in these tumors. For example, trastuzumab deruxtecan was explored in patients who were HER2-lowpositive. We saw that the objective response rates [ORRs] were almost 40% in this population; this response was similar for patients who had HER2 1+ disease compared with HER2 2+ disease; these data suggest very impressive efficacy in this subgroup.

Many of us have been a little bit perplexed about why some drugs work for HER2-lowpositive disease and others don't. For example, [when using] trastuzumab deruxtecan, we're seeing an almost 40% ORR, but we did not see significant responses with T-DM1 in subsets of HER2-lowpositive patients. Why is this? We truthfully don't have the answer, but it may be that you're delivering more chemotherapy with trastuzumab deruxtecan than you are with T-DM1. Perhaps that's why you need just a bit of HER2 expression to get that binding of the ADC and get the drug into the cancer cell.

We have also seen this with other novel ADCs, such as [vic-]trastuzumab duocarmazine [SYD985], where we've also seen ORRs between 25% and 30% in HER2-lowpositive disease. Again, this is very promising and there are lots of other drugs in development that are being studied in this setting, such as new bispecific antibodies. Were going to see many more [treatments] come in this space. There is even a registration trial ongoing with trastuzumab deruxtecan compared with standard chemotherapy for HER2-lowpositive patients.

Right now, testing for these breast cancers is really quite rudimentary and is via IHC. If a patient is HER2 1+, they would be HER2low-positive and if they are HER2 2+ but not FISH-amplified, they would be HER2low-positive. We need to see if there are better tests that can be done to detect very low levels of HER2 expression, because there may be some patients who have tumors [that dont show any positivity but have] low levels of expression that just don't quite meet criteria to be HER2 1+ that may benefit from some of these novel ADCs.

Right now, I'm very excited about the ongoing registration study for trastuzumab deruxtecan compared with physicians choice for patients who have received 1 or 2 prior chemotherapies for metastatic HER2-lowpositive breast cancer. Seeing ORRs that are near 40%, at least in the early single-arm studies, makes us quite excited about the potential to get this level of activity. This would be a nice opportunity for patients to get more personalized treatment that could improve their outcomes.

We've seen a lot of very interesting data come out about approaches to take for patients who have early-stage, HER2-positive disease. Prior to 2 or 3 years ago, we were predominantly treating patients in the adjuvant setting with HER2-directed therapy, but we have since learned that it's quite critical to give the majority of our patients preoperative therapy because we can adapt postoperative treatment to improve outcomes.

Data have evolved over the last year, and we've learned that giving adjuvant ado-trastuzumab emtansine [T-DM1; Kadcyla] can improve outcomes for patients with residual disease after neoadjuvant HER2-directed therapy.

Also, we can augment outcomes for patients by adding an additional biologic therapy, such as pertuzumab [Perjeta], to our patients who are getting chemotherapy and trastuzumab [Herceptin]. We certainly have a lot of tools added to our toolbox, but we've been trying to refine that even further. That's what the focus of a lot of the more recent developments have been on. Now that we have all of these very effective biologic therapies, can we potentially de-escalate therapy for patients who may be at lower risk? Can we potentially escalate therapy for those who may be of a higher clinical risk?

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Tolaney Touches on HER2+ -Low Breast Cancer Testing, Possibilities, and Challenges - OncLive

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